Utility of a Herpes Oncolytic Virus for the Detection of Neural Invasion By Cancer1

Prostate, pancreatic, and head and neck carcinomas have a high propensity to invade nerves. Surgical resection is a treatment modality for these patients, but it may incur significant deficits. The development of an imaging method able to detect neural invasion (NI) by cancer cells may guide surgical resection and facilitate preservation of normal nerves. We describe an imaging method for the detection of NI using a herpes simplex virus, NV1066, carrying tyrosine kinase and enhanced green fluorescent protein (eGFP). Infection of pancreatic (MiaPaCa2), prostate (PC3 and DU145), and adenoid cystic carcinoma (ACC3) cell lines with NV1066 induced a high expression of eGFP in vitro. An in vivo murine model of NI was established by implanting tumors into the sciatic nerves of nude mice. Nerves were then injected with NV1066, and infection was confirmed by polymerase chain reaction. Positron emission tomography with [18F]-2′-fluoro-2′-deoxyarabinofuranosyl-5-ethyluracil performed showed significantly higher uptake in NI than in control animals. Intraoperative fluorescent stereoscopic imaging revealed eGFP signal in NI treated with NV1066. These findings show that NV1066 may be an imaging method to enhance the detection of nerves infiltrated by cancer cells. This method may improve the diagnosis and treatment of patients with neurotrophic cancers by reducing injury to normal nerves and facilitating identification of infiltrated nerves requiring resection

Minimum Nodal Yield in Oral Squamous Cell Carcinoma: Defining the Standard of Care in a Multicenter International Pooled Validation Study

Purpose. There is evidence to suggest that a nodal yield <18 is an independent prognostic factor in patients with clinically node negative (cN0) oral squamous cell carcinoma (SCC) treated with elective neck dissection (END). We sought to evaluate this hypothesis with external validation and to investigate for heterogeneity between institutions. Patients and Methods. We analyzed pooled individual data from 1,567 patients treated at nine comprehensive cancer centers worldwide between 1970 and 2011. Nodal yield was assessed with Cox proportional hazard models, stratified by study center, and adjusted for age, sex, pathological T and N stage, margin status, extracapsular nodal spread, time period of primary treatment, and adjuvant therapy. Two-stage random-effects meta-analyses were used to investigate for heterogeneity between institutions. Results. In multivariable analyses of patients undergoing selective neck dissection, nodal yield <18 was associated with reduced overall survival [hazard ratio (HR) 1.69; 95 % confidence interval (CI) 1.22-2.34; p = 0.002] and disease-specific survival (HR 1.88; 95 % CI 1.21-2.91; p = 0.005), and increased risk of locoregional recurrence (HR 1.53; 95 % CI 1.04-2.26; p = 0.032). Despite significant differences between institutions in terms of patient clinicopathological factors, nodal yield, and outcomes, random-effects meta-analysis demonstrated no evidence of heterogeneity between centers in regards to the impact of nodal yield on disease-specific survival (p = 0.663; I-2 statistic = 0). Conclusion. Our data confirm that nodal yield is a robust independent prognostic factor in patients undergoing END for cN0 oral SCC, and may be applied irrespective of the underlying patient population and treating institution. A minimum adequate lymphadenectomy in this setting should include at least 18 nodes

Improvement in Survival of Patients With Oral Cavity Squamous Cell Carcinoma

BACKGROUND: An association between the survival of patients with oral cavity squamous cell carcinoma (OCSCC) and advancements in diagnosis and therapy has not been established. METHODSThis was a retrospective, longitudinal, international, population-based study of 2738 patients who underwent resection of OCSCC during 2 different decades. Characteristics of patients from 7 international cancer centers who received treatment between 1990 and 2000 (group A; n=735) were compared with patients who received treatment between 2001 and 2011 (group B; n=2003). RESULTSPatients in group B had more advanced tumors and tended to develop distant metastases more frequently than patients in group A (P=.005). More group B patients underwent selective neck dissection and received adjuvant radiotherapy (P<.001). Outcome analysis revealed a significant improvement in 5-year overall survival, from 59% for group A to 70% for group B (P<.001). There was also a significant improvement in disease-specific survival associated with operations performed before and after 2000 (from 69% to 81%, respectively; P<.001). Surgery after 2000, negative margins, adjuvant treatment, and early stage disease were independent predictors of a better outcome in multivariate analysis. The decade of treatment was an independent prognostic factor for cancer-specific mortality (hazard ratio, 0.42; 95% confidence interval, 0.3-0.6). CONCLUSIONSThe survival rate of patients with OCSCC improved significantly during the past 2 decades despite older age, more advanced disease stage, and a higher rate of distant metastases. The current results suggest that the prognosis for patients with OCSCC has improved over time, presumably because of advances in imaging and therapy. Cancer 2013;119:4242-4248. (c) 2013 American Cancer Society

Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion : an international multicenter retrospective study

Importance: The current American Joint Committee on Cancer (AJCC) staging system for oral cancer demonstrates wide prognostic variability within each primary tumor stage and provides suboptimal staging and prognostic information for some patients. Objective: To determine if a modified staging system for oral cancer that integrates depth of invasion (DOI) into the T categories improves prognostic performance compared with the current AJCC T staging. Design, setting, and participants: Retrospective analysis of 3149 patients with oral squamous cell carcinoma treated with curative intent at 11 comprehensive cancer centers worldwide between 1990 and 2011 with surgery ± adjuvant therapy, with a median follow-up of 40 months. Main outcomes and measures: We assessed the impact of DOI on disease-specific and overall survival in multivariable Cox proportional hazard models and investigated for institutional heterogeneity using 2-stage random effects meta-analyses. Candidate staging systems were developed after identification of optimal DOI cutpoints within each AJCC T category using the Akaike information criterion (AIC) and likelihood ratio tests. Staging systems were evaluated using the Harrel concordance index (C-index), AIC, and visual inspection for stratification into distinct prognostic categories, with internal validation using bootstrapping techniques. Results: The mean and median DOI were 12.9 mm and 10.0 mm, respectively. On multivariable analysis, DOI was a significantly associated with disease-specific survival (P < .001), demonstrated no institutional prognostic heterogeneity (I² = 6.3%; P = .38), and resulted in improved model fit compared with T category alone (lower AIC, P < .001). Optimal cutpoints of 5 mm in T1 and 10 mm in T2-4 category disease were used to develop a modified T staging system that was preferred to the AJCC system on the basis of lower AIC, visual inspection of Kaplan-Meier curves, and significant improvement in bootstrapped C-index. Conclusions and relevance: We propose an improved oral cancer T staging system based on incorporation of DOI that should be considered in future versions of the AJCC staging system after external validation.11 page(s

The Prognosis of N2b and N2c Lymph Node Disease in Oral Squamous Cell Carcinoma Is Determined by the Number of Metastatic Lymph Nodes Rather Than Laterality

BACKGROUND: A study was conducted to assess for prognostic heterogeneity within the N2b and N2c classifications for oral cancer based on the number of metastatic lymph nodes and to determine whether laterality of neck disease provides additional prognostic information. METHODS: An international multicenter study of 3704 patients with oral cancer undergoing surgery with curative intent was performed. The endpoints of interest were disease-specific survival and overall survival. Model fit was assessed by the Akaike Information Criterion and comparison of models with and without the covariate of interest using a likelihood ratio test. RESULTS: The median number of metastatic lymph nodes was significantly higher in patients with N2c disease compared to those with N2b disease (P = 5) in patients with both N2b and N2c disease (P < .001). A proposed reclassification combining N2b and N2c disease based on the number of metastatic lymph nodes demonstrated significant improvement in prognostic accuracy compared with the American Joint Committee on Cancer staging system, and no improvement was noted with the addition of a covariate for contralateral or bilateral neck disease (P = .472). CONCLUSIONS: The prognosis of patients with oral cancer with N2b and N2c disease appears to be similar after adequate adjustment for the burden of lymph node metastases, irrespective of laterality. Based on this finding, the authors propose a modified lymph node staging system that requires external validation before implementation in clinical practice. (C) 2014 American Cancer Society

Depth of invasion alone as an indication for postoperative radiotherapy in small oral squamous cell carcinomas: An International Collaborative Study

Background We aimed to investigate whether depth of invasion (DOI) should be an independent indication for postoperative radiotherapy (PORT) in small oral squamous cell carcinomas (SCC). Methods Retrospective analysis of DOI (= 10 mm) and disease-specific survival (DSS) in a multi-institutional international cohort of 1409 patients with oral SCC = 10 mm, 8% with DOI 5-10 mm, and 6% with DOI <5 mm (P = .169), yielding an absolute risk difference of only 4%. Conclusion The deterioration in prognosis with increasing DOI largely reflects an association with other adverse features. In the absence of these, depth alone should not be an indication for PORT outside a clinical trial